U.S. Pat. No. 4,424,208, issued Jan. 3, 1984 to Wallace et al., and commonly owned by the assignee of the present application, discloses an injectable implant material for soft tissue augmentation comprising a dispersion of particles of crosslinked atelopeptide collagen and reconstituted fibrous atelopeptide collagen in a physiologically acceptable aqueous carrier.
Commonly owned U.S. Pat. No. 4,582,640, issued Apr. 15, 1986 to Smestad et al., discloses glutaraldehyde-crosslinked collagen compositions and processes for preparing such compositions which comprise reconstituting atelopeptide collagen from solution by neutralizing the solution at a reduced temperature and a hypotonic ionic strength, crosslinking the reconstituted collagen fibers in an aqueous medium at a concentration of 0.1 to 10 mg/ml with glutaraldehyde, followed by separating the crosslinked collagen from the reaction mixture. Commonly owned U.S. Pat. No. 4,642,117, issued Feb. 10, 1987 to Nguyen et al., discloses an injectable collagen material comprised of reconstituted, mechanically sheared atelopeptide fibers obtained by passing the fibers repeatedly through a rigid mesh screen. The mechanically sheared collagen fibers may be further crosslinked, for example, with glutaraldehyde, to improve implant characteristics.
Commonly owned U.S. Pat. No. 5,162,430, issued Nov. 10, 1992 to Rhee et al., discloses collagen-synthetic polymer conjugates and methods of covalently binding collagen to synthetic hydrophilic polymers. Also disclosed in U.S. Pat. No. 5,162,430 is the general concept of conjugating to a synthetic hydrophilic polymer a collagen material that had previously been crosslinked using a chemical crosslinking agent, such as glutaraldehyde.
Commonly owned U.S. Pat. No. 5,292,802, issued Mar. 8, 1994 to Rhee et al., discloses methods for making tubes comprising collagen-synthetic polymer conjugates. Commonly owned U.S. Pat. No, 5,306,500, issued Apr. 26, 1994 to Rhee et al., discloses methods of augmenting tissue with collagen-synthetic polymer conjugates.
Commonly owned U.S. Pat. No. 5,328,955, issued Jul. 12, 1994 to Rhee et al., discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. Commonly owned, copending U.S. application Ser. No. 07/984,933, filed Dec. 2, 1992, discloses methods for coating implants with collagen-synthetic polymer conjugates.
Commonly owned, copending U.S. application Ser. No. 08/146,843, filed Nov. 3, 1993, discloses conjugates comprising various species of glycosaminoglycan covalently bound to synthetic hydrophilic polymers, which are optionally bound to collagen as well. Commonly owned, copending U.S. application Ser. No. 08/147,227, filed Nov. 3, 1993, discloses collagen-polymer conjugates comprising chemically modified collagens such as, for example, succinylated collagen or methylated collagen, covalently bound to synthetic hydrophilic polymers to produce optically clear materials for use in ophthalmic or other medical applications.
Commonly owned U.S. application Ser. No. 08/236,769, filed May 2, 1994, discloses collagen-synthetic polymer matrices prepared using a multiple step reaction. Commonly owned U.S. application Ser. No. 08/287,549, filed Aug. 8, 1994, discloses a method of preparing crosslinked biomaterial compositions, for use in tissue augmentation or the production of various formed implants, which method comprises mixing collagen or another biocompatible polymer with a sterile synthetic hydrophilic polymer in dry form. Also disclosed are methods of preparing dry crosslinking agents in sterile form packaged in syringes.
All publications cited above and herein are incorporated herein by reference to describe and disclose the subject matter for which it is cited.
In our earlier patents and applications, we disclosed compositions comprising synthetic hydrophilic polymers, usually various types of functionally activated polyethylene glycol (PEG), chemically conjugated to inert biomaterials, including collagen and glycosaminoglycans. A consistent problem has been encountered with such PEG-crosslinked biomaterial compositions in that the forms of activated PEG which are most useful in the formation of crosslinked collagen materials having high gel strengths tend to exhibit very short cure times (i.e., the amount of time required for a material to attain a specified value of elastic modulus or gel stiffness). For a physician providing soft tissue augmentation in the face, such as filling in wrinkles or scars, the cure time of a composition corresponds to the maximum amount of time that the material can be extruded from the needle and manipulated beneath the patient's skin following injection to minimize visible lumping and beading of the material. Short cure times result in inconveniently blocked needles and may result in unsightly (though temporary) lumps in the patient's skin due to material that has not been well distributed within the dermis.
We now disclose a detailed description of preferred embodiments of the present invention, including injectable crosslinked collagen compositions having controlled cure times and methods of using such compositions to effect augmentation of soft or hard tissue.